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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents

ID: 723973.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
Cardiac-Specific Activation of IKK2 Leads to Defects in Heart Development and Embryonic Lethality
Authors:Kraut, B.; Maier, H. J.; Kokai, E.; Fiedler, K.; Boettger, T.; Illing, A.; Kostin, S.; Walther, P.; Braun, T.; Wirth, T.
Date of Publication (YYYY-MM-DD):2015
Title of Journal:PLoS ONE
Issue / Number:11
Start Page:e0141591
Audience:Not Specified
Abstract / Description:The transcription factor NF-kappaB has been associated with a range of pathological conditions of the heart, mainly based on its function as a master regulator of inflammation and pro-survival factor. Here, we addressed the question what effects activation of NF-kappaB can have during murine heart development. We expressed a constitutively active (CA) mutant of IKK2, the kinase activating canonical NF-kappaB signaling, specifically in cardiomyocytes under the control of the alpha-myosin heavy chain promoter. Expression of IKK2-CA resulted in embryonic lethality around E13. Embryos showed defects in compact zone formation and the contractile apparatus, and overall were characterized by widespread inflammation with infiltration of myeloid cells. Gene expression analysis suggested an interferon type I signature, with increased expression of interferon regulatory factors. While apoptosis of cardiomyocytes was only increased at later stages, their proliferation was decreased early on, providing an explanation for the disturbed compact zone formation. Mechanistically, this could be explained by activation of the JAK/STAT axis and increased expression of the cell cycle inhibitor p21. A rescue experiment with an IkappaBalpha superrepressor demonstrated that the phenotype was dependent on NF-kappaB. We conclude that activation of NF-kappaB is detrimental during normal heart development due to excessive activation of pro-inflammatory pathways.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. Institute of Molecular Medicine, University of Ulm, Ulm, Germany. Core Facility Electron Microscopy, University of Ulm, Ulm, Germany.
Identifiers:ISSN:1932-6203 (Electronic) 1932-6203 (Linking) %R 10.1371/journal.pone.0141591
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